This is a competing continuation proposal for the four-year project #AI42361, previously entitled, "Genetics of An. gambiae susceptibility to Plasmodium." Since its inception, this project has comprised the first systematic examination of mechanisms of mosquito immunity and resistance to Plasmodium in nature. Understanding the biology of these interactions could permit development of novel strategies to inhibit parasite transmission. In the last project period, we carried out a field-based genetic analysis of the major human malaria vector, Anopheles gambiae. This work for the first time identified genes in An. gambiae that reduce the natural transmission of P. falciparum. We mapped two loci for parasite resistance, Pfin1 and Pfin2. Resistant homozygotes at the Pfin1 locus had a mean of 0.17 oocysts per mosquito, while susceptible homozygotes had 50.6. We found an apparent high natural frequency of resistance alleles, which suggests that malaria parasites (or a similar pathogen) exert a significant selective pressure on vector populations. Here, we present new integrated Aims that build directly upon the previous work to study the genetics and genomics of mosquito immunity and parasite resistance in the context of the natural malaria transmission system. We will: 1) Screen a natural population of An. gambiae by genome-wide scanning at 10 cM resolution for loci that control resistance to P. falciparum in the natural transmission system in Mali, West Africa. 2) Map natural resistance loci identified in Aim 1 at high genetic resolution to isolate a tractable number of candidate resistance genes. 3) Filter the candidate resistance genes by sequence analysis, transcriptional profiling, and physiological studies, and positionally clone at least one resistance trait gone. The proposed continuation project will be the first genetic screen in a mosquito field population for genes conferring resistance to malaria parasites. We will determine the number, frequencies, and genomic organization of parasite-resistance traits, at 10 cM genetic resolution. We will maintain mosquito families segregating chosen traits and we may select stable lines, we will map the traits, describe the cellular mechanism, and we will positionally clone one or more underlying genes.